Background: Despite the extensive use of the gonadotropin-releasing hormone (GnRH) antagonist protocol in treating infertile women, particularly those with polycystic ovary syndrome (PCOS), there have not been sufficient evidence to compare the flexible and fixed variants in in vitro fertilization (IVF) cycles.

Objective: This study aims to assess the treatment outcomes of flexible and fixed types of GnRH-antagonist protocol for IVF in women with PCOS.

Materials and Methods: In this randomized clinical trial, 150 infertile women with PCOS, who were candidates for IVF, and referred to the Yazd Research and Clinical Center for Infertility, Yazd, Iran between October 2023 and February 2024 were included. Participants were divided into 2 groups (n = 75/ each) based on the type of antagonist protocol (fixed or flexible). GnRH antagonist administration started on the 5th day of gonadotropin treatment in the fixed group. In the flexible group when there was at least one follicle 12–14 mm, GnRH antagonist was started. Finally, the number of metaphase II oocyte, the quality of embryos, the duration of the stimulation cycle, the dose of gonadotropin, the number of GnRH-antagonist, and the rate of ovarian hyperstimulation syndrome were evaluated.

Results: No statistically significant difference was observed in terms of cycle length and the total dose of gonadotropin between groups. Nevertheless, a notable distinction was observed in the total number of oocytes (17.84 vs. 15.5, p = 0.023) and mature oocytes (13.64 vs. 11.83, p = 0.019) in the flexible group compared to the fixed group.

Conclusion: In conclusion, the IVF outcomes are more favorable in women with PCOS undergoing the flexible GnRH-antagonist protocol compared to the fixed protocol.

Key words: Gonadotropin-releasing hormone, Polycystic ovary syndrome, Fertilization in vitro, Oocytes.

[1] Si M, Qi X, Zhen X, Yang Ch, Tian T, Long X, et al. Dose nomogram of individualization of the initial follicle-stimulating hormone dosage for patients with polycystic ovary syndrome undergoing IVF/ICSI with the GnRH-ant protocol: A retrospective cohort study. Adv Ther 2023; 40: 3971–3985.

[2] Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: Pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc 2020; 3: 1545–1573.

[3] Hu Zh, Zeng R, Gao R, Chen M, Liu X, Zhang Q, et al. Effects of different gonadotropin preparations in GnRH antagonist protocol for patients with polycystic ovary syndrome during IVF/ICSI: A retrospective cohort study. Front Endocrinol 2024; 15: 1309993.

[4] Eftekhar M, Bagheri RB, Neghab N, Hosseinisadat R. Evaluation of pretreatment with cetrotide in an antagonist protocol for patients with PCOS undergoing IVF/ICSI cycles: A randomized clinical trial. JBRA Assist Reprod 2018; 22: 238–243.

[5] Hosseini Rashidi B, Behrouzi Lak T, Shahrokh Tehrani E, Davari Tanha F. Fixed versus flexible gonadotropin releasing hormone antagonist protocol in controlled ovarian stimulation for invitro fertilization in women with polycystic ovary syndrome. J Family Reprod Health 2015; 9: 141–146.

[6] Shin JJ, Park KE, Choi YM, Kim H-O, Choi D-H, Lee WS, et al. Early gonadotropin-releasing hormone antagonist protocol in women with polycystic ovary syndrome: A preliminary randomized trial. Clin Exp Reprod Med 2018; 45: 135–142.

[7] Yanagihara Y, Tanaka A, Nagayoshi M, Tanaka I, Shinohara R, Fukushima F, et al. A modified GnRH antagonist method in combination with letrozole, cabergoline, and GnRH antagonist for PCOS: Safe and effective ovarian stimulation to treat PCOS and prevent OHSS. Reprod Med Biol 2022; 21: e12429.

[8] Zhang W, Xie D, Zhang H, Huang J, Xiao X, Wang B, et al. Cumulative live birth rates after the first ART cycle using flexible GnRH antagonist protocol vs. standard long GnRH agonist protocol: A retrospective cohort study in women of different ages and various ovarian reserve. Front Endocrinal 2020; 11: 287.

[9] Luo X, Pei L, Li F, Li C, Huang G, Ye H. Fixed versus flexible antagonist protocol in women with predicted high ovarian response except PCOS: A randomized controlled trial. BMC Pregnancy Childbirth 2021; 21: 348.

[10] Venetis C, Storr A, Chua S, Mol B, Longobardi S, Yin X, et al. What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis. Hum Reprod Update 2023; 29: 307–326.

[11] Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.

[12] Rao KA, Rao VA, Devi R. Principles and practice of assisted reproductive technology: 3rd Ed. United Kingdom: Jaypee brothers’ medical publishers; 2023.

[13] Dokras A, Sargent IL, Barlow DH. Fertilization and early embryology: Human blastocyst grading: An indicator of developmental potential? Hum Reprod 1993; 8: 2119–2127.

[14] Al-Inany H, Aboulghar MA, Mansour RT, Serour GI. Optimizing GnRH antagonist administration: Meta-analysis of fixed versus flexible protocol. Reprod Biomed Online 2005; 10: 567–570.

[15] Escudero E, Bosch E, Crespo J, Simón C, Remohi?J, Pellicer A. Comparison of two different starting multiple dose gonadotropin-releasing hormone antagonist protocols in a selected group of in vitro fertilization-embryo transfer patients. Fertil Steril 2004; 81: 562–566.

[16] Ludwig M, Katalinic A, Banz C, Schröder AK, Löning M, Weiss JM, et al. Tailoring the GnRH antagonist cetrorelix acetate to individual patients’ needs in ovarian stimulation for IVF: Results of a prospective, randomized study. Hum Reprod 2002; 17: 2842–2845.

[17] Mochtar MH, Dutch Ganirelix Study Group. The effect of an individualized GnRH antagonist protocol on folliculogenesis in IVF/ICSI. Hum Reprod 2004; 19: 1713–1718.

[18] Kolibianakis EM, Albano C, Kahn J, Camus M, Tournaye H, Van Steirteghem AC, et al. Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy. Fertil Steril 2003; 79: 873–880.

[19] Ioannidou P, Bosdou J, Kolibianaki E, Lainas G, Lainas T, Grimbizis G, et al. A higher probability of ongoing pregnancy is present by using the fixed as compared to the flexible GnRH antagonist protocol. Hum Reprod 2022; 37 (Suppl.): i473-i474.

[20] Han Q-S, Zhou Y, Xu Y, Ai K-L, Song J-Y, Sun Z-G. Optimal timing of GnRH antagonist initiation in IVF-ET: A retrospective cohort study on advanced maternal age women. Front Endocrinol 2024; 15: 1340230.

[21] Wang Y, Zhang M, Shi H, Yi S, Li Q, Su Y, et al. Causes and effects of oocyte retrieval difficulties: A retrospective study of 10,624 cycles. Front Endocrinol 2022; 12: 564344.

[22] Kolibianakis EM, Venetis CA, Kalogeropoulou L, Papanikolaou E, Tarlatzis BC. Fixed versus flexible gonadotropin-releasing hormone antagonist administration in in vitro fertilization: A randomized controlled trial. Fertil Steril 2011; 95: 558–562.